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Peroral Famciclovir in the Treatment of Experimental Ultraviolet Radiation-Induced Herpes Simplex Labialis: A Double-Blind, Dose-Ranging, Placebo-Controlled, Multicenter Trial

  1. Spotswood L. Spruance,
  2. Nathaniel H. Rowe,
  3. G. Wayne Raborn,
  4. Edward A. Thibodeau,
  5. Joseph A. D'Ambrosio and
  6. David I. Bernstein1
  1. Department of Medicine, School of Medicine, University of Utah, Salt Lake City; Department of Oral Medicine/Pathology/Surgery, School of Dentistry, and Department of Pathology, School of Medicine, University of Michigan, Ann Arbor; Faculty of Medicine and Oral Health Sciences, University of Alberta, Edmonton, Canada; School of Dental Medicine, University of Connecticut, Farmington; J. N. Gamble Institute of Medical Research, Cincinnati, Ohio
  1. Reprints or correspondence: Dr. S. L. Spruance, Division of Infectious Diseases, School of Medicine 4B319, University of Utah, 50 N. Medical Dr., Salt Lake City, UT 84132.

  1. Presented in part: 35th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, 17–20 September 1995 (abstract H144).

  • ↵1 Present affiliation: Division of Infectious Diseases, Children's Hospital Medical Center, Cincinnati.

 
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Abstract

Three doses of famciclovir were tested for treatment of experimental ultraviolet radiation (UVR)-induced herpes labialis. Patients received 125, 250, or 500 mg of famciclovir or placebo 3 times a day for 5 days beginning 48 h after UVR exposure, a model of early episodic intervention. Of 248 patients irradiated, 102 developed lesions while on treatment. There were no significant differences between groups in the number of lesions. The mean maximal lesion size was reduced in a dose-proportional manner: 139, 105, 77, and 55 mm2 for the placebo and 125-, 250-, and 500-mg famciclovir groups, respectively (P = .040, linear regression). Median time to healing was faster in the 500-mg famciclovir group than in the placebo group, both by investigator (4 vs. 6 days, 33% reduction, P = .010) and patient assessment (3.0 vs. 5.8 days, 48% reduction, P = .008) analyses. These findings suggest that evaluation of higher drug doses for herpes labialis treatment is warranted.

The natural history of herpes labialis in immunocompetent persons imposes limitations on what can be accomplished by acute therapeutic intervention in an evolving recurrent episode. Because of the antiviral activity of a healthy secondary immune response [1, 2], maximum lesion severity (size, pain, and virus titer) occurs rapidly, often within 8 h of onset [3], and the duration of the illness is brief. Accordingly, the therapeutic window of opportunity is narrow. Patients must be forearmed with medication and vigilant for the earliest signs and symptoms of a recurrence to realize a gain from treatment. Because of these inherent difficulties, it is important to maximize all aspects of antiviral therapy.

Multiple factors can influence the effect of antiviral agents on herpes simplex virus (HSV) infections, including the mode of action of the antiviral [4]; the multiplicity of infection (moi; number of input virions/cell) [5, 6]; the timing of drug administration in relationship to the viral replication cycle [7]; cell type [8], by virtue of multiple influences including the magnitude of thymidine pools [9–11], thymidine kinase activity [12], and drug catabolism by thymidine phosphorylase [13]; and the pharmacokinetics of the drug systemically, locally, or intracellularly [14–16]. The initiation, duration, magnitude, and frequency of antiviral drug dosing for herpes labialis should be carefully considered with these factors in mind.

The influence of the mode of action of antiviral drugs and the moi are easy to demonstrate experimentally. Primary cultures of sympathetic neurons from prenatal rats were completely protected by 50 μM acyclovir from HSV-1 infection at an moi of 1–5, but moi of 10–20 led to death of the cultures even in the presence of 500 μM acyclovir [17]. One of us (S.L.S.) and his associate infected mink lung cells with an moi of 0.0001–0.5 of HSV-1 E1 15 (an acyclovir-sensitive strain) in a liquid medium containing 0, 4, 20, or 200 μM acyclovir and followed cytopathic effects for 3 days. With the lowest moi (0.0001), all drug concentrations prevented cytopathic effects. At an moi 10-fold higher (0.001), the lowest concentration of acyclovir (4 μM) began to fail; at an moi 100-fold higher (0.01), both 4 and 20 μM acyclovir failed; and when the moi was ⩾0.25, infection eventually led to complete loss of the monolayer regardless of the drug concentration [18]. The reason for these relationships is that nucleoside analogue antiviral drugs, such as acyclovir, cannot prevent the death of a cell once it is infected with HSV, but instead acts by reducing the number of infectious virions generated and slowing the spread of infection between cells [18]. If all cells are infected prior to addition of the antiviral drug (high moi), then even high concentrations of drug will have no benefit.

We have hypothesized that the moi is high in herpes labialis and that this could be one reason for the limited activity of small doses of antiviral drugs against this disease [4]. Famciclovir (Famvir; SmithKline Beecham, Philadelphia) is the oral form of the antiviral agent, penciclovir, and is currently marketed worldwide for the treatment of herpes zoster and herpes genitalis. In the present study, we tested our hypothesis by performing a dose-ranging study of the efficacy of peroral famciclovir in the treatment of ultraviolet radiation (UVR)-induced herpes labialis.

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Methods

Study design

Patients with a history of sunlight-induced herpes labialis were located by advertisement and screened for eligibility as detailed below. Patients were exposed to UVR on the lips to induce a recurrence of herpes labialis and given study medication for 5 days beginning 48 h after UVR exposure. This procedure is considered an idealized model of acute, episodic therapy [19]. Patients were randomized in a double-blind fashion to receive 1 of 3 doses of famciclovir or placebo. Patients were allocated equally to the 4 treatment groups.

Study medication

Study medication was provided as white film-coated tablets containing 125, 250, or 500 mg of famciclovir or matching placebo. All tablets were identical in shape, weight, and color. Tablets were dispensed in blister cards, and 1 tablet was taken 3 times a day for 5 days beginning 48 h after UVR exposure.

Patient population

Investigators at five academic medical centers in the United States and Canada recruited study subjects. To be eligible, a person had to be ⩾ 18 years old and have had a self-described history of recurrent herpes labialis (vesicular lesions on the vermilion border of the lips or perioral skin) following sun exposure. In addition, women of childbearing age must have been using an accepted method of birth control. Subjects were not eligible if they were pregnant or breast-feeding, had a history or laboratory evidence of a significant medical disorder, had received any antiviral drug, investigational drug or vaccine, had an episode of herpes labialis within 30 days before enrollment, or had a psychiatric disorder or were considered unreliable or unable to follow protocol directions in the opinion of the investigator.

Study procedures

Patients were screened to determine if they fulfilled all inclusion and exclusion criteria. This included a pre-enrollment urine or serum pregnancy test for female patients of childbearing potential. A full medical history was recorded and a physical examination performed. Blood samples for hematologic and serum chemistry determinations were taken, and a urine sample was collected for dipstick analysis. An additional serum sample was drawn for possible future serology testing. Beginning the same day or within 1 week of the screening visit, the patient's sensitivity to UVR was evaluated by determination of the minimal erythema dose (MED), as described below. After completion of the MED determination or within 1 week, patients underwent UVR exposure of the lips as described below (study day 1). Patients took study medication for 5 days beginning 48 h after UVR exposure. Patients returned to the clinic on days 3–7 post-UVR exposure and were evaluated for the development of lesions as described below. If lesions developed, the patients were followed daily until the hard crust stage, then every other day until loss of crusts. In addition, patients maintained a diary in which they recorded their assessment of lesion stage and pain 4 times a day until lesion healing. A final visit to assess posttreatment lesions and repeat laboratory tests was done between days 13–15 post-UVR exposure.

Determination of MED

Six small circular 1-cm in diameter areas of each patient's ventral forearm were exposed to UVR from two fluorescent tubes as previously described [19]. The shortest duration of exposure producing a homogeneous erythematous reaction with distinct margins 24 h later was defined as 1 MED. Patients who did not have a reaction from any exposure were arbitrarily assigned an MED of 6 min.

Exposure of the lips to UVR

For each subject, half of the area of the lips (the usual site of recurrent herpes labialis) was outlined with a black marking pen. The remainder of the lips and perioral skin outside this zone was covered with a para-amino benzoic acid sunscreen having a sun protection factor of 15. The patient was then irradiated with 4 MED of UVR by increasing the duration of exposure [19].

Evaluation of lesions

In experimental UVR-induced herpes labialis, patients may develop “immediate lesions” within 6–48 h post-UVR exposure or “delayed” lesions 3–7 days after exposure [19]. Immediate lesions are of uncertain pathogenesis and have not responded to antiviral drugs in prior studies [19, 20]. Delayed lesions are thought to develop from virus reactivation in the trigeminal nerve, centrifugal axonal virus transport, and seeding of the epidermis in the irradiated zone. Delayed lesions have been completely prevented by peroral acyclovir begun on or before the day of UVR exposure, but when acyclovir treatment was delayed until 48 h after UVR exposure, delayed lesions developed, but their severity was reduced compared with lesions developing in placebo-treated subjects [19]. The use of drug intervention 48 h after UVR is considered an idealized model of acute, episodic therapy in that the antiviral agent is present at the very earliest moments of delayed lesion development.

Documentation of immediate lesions was not a formal part of this protocol, but the Utah site electively recorded this information for their patients. The first delayed lesion to develop in the treatment period was termed the “primary” delayed lesion. Delayed lesions that developed on subsequent days of the treatment after a primary lesion that were located >1 cm from the primary lesions were termed “secondary lesions.” Lesions developing on subsequent days that were within 1 cm of the primary lesions were considered an extension of the primary lesion and were included in the primary lesion evaluation. Posttreatment lesions were those occurring on days 8–14 post-UVR exposure. Lesions were further categorized as “aborted” if they progressed no further than the papule stage and “classical” if they developed into vesicles, ulcers, or hard crusts. Clinical assessment of primary delayed lesion severity was made by observation of lesion stage, size, and pain by previously described criteria [21]. Secondary and posttreatment lesions were noted but not measured or followed.

Virus isolation

Lesion specimens for virus isolation were taken during the vesicle and ulcer stages only by breaking open vesicles with a sterile needle and absorbing the fluid into a cotton swab and by rubbing the base of ulcers with a media-moistened swab. Swabs were placed into 2 mL of viral transport medium and processed for virus isolation as described below. Lesion specimens in viral transport medium were used to inoculate monolayers of susceptible cells. The presence of HSV in the specimen was determined by the appearance of typical cytopathic effects.

Data analysis

All patients who received ⩾ 1 dose of medication were included in the intent-to-treat population. The primary efficacy variables were the proportion of patients who developed delayed lesions and the time to healing of primary delayed classical lesions. Secondary variables included the proportion of patients with pain, time to loss of pain, the proportion of patients with a positive virus culture, the maximum lesion area, and the duration of the individual lesion stages.

The proportions of patients in each treatment group that developed an event were compared by Fisher's exact test. The analyses of time to events were done using Cox's proportional-hazards model available in SAS software (SAS Institute, Cary NC), and probability determinations were adjusted for multiple comparisons [22]. For time-to-event analyses, time zero began upon the appearance of the event in question (vesicle, pain, crust). Other measures of lesion severity (continuous variables) were examined by the Mann-Whitney rank sum test. Dose-response of outcome variables was examined by linear regression among the 3 active treatment groups. All probability determinations were two-tailed and P<.05 was considered significant.

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Results

Characteristics of the study population

In total, 243 subjects were randomly assigned to study treatment and took study medication. They comprised the intent-to-treat population. The demographic data and medication compliance for these patients are summarized in table 1. There were no significant differences among the 4 treatment groups. Most subjects were female and Caucasian. Age range was 18–68 years (mean, 35). The mean time with herpes labialis was 20 years and the mean number of outbreaks in the preceding year was 4.7 episodes. Compliance with study medication was excellent.

UVR exposure

The duration of UVR exposure was similar among all treatment groups. The mean number of minutes of UVR exposure in the overall population was 20 (range, 4–24). There was no difference in the duration of UVR exposure between those who developed lesions and those who did not (data not shown). The procedure was well-tolerated and no patients withdrew from the study because of UVR-related reactions.

Development of lesions

Forty-two percent (102/243) of the patients developed primary delayed lesions (lesions that developed between 48 h and 7 days after UVR exposure; table 2). Of these 102 patients, 87 developed primary delayed classical lesions and 15 developed primary delayed aborted lesions. The primary delayed classical lesions developed within the zone of UVR exposure in 90% of the subjects. Secondary lesions, distant from the primary lesions and occurring during the treatment period ⩾1 day after the primary lesion, developed in 19 patients. Twenty-two (9%) of the 243 patients developed “post-treatment” lesions at days 8–15, similar to the expected number of lesions in 1 week among our study population based on their historical lesion frequency (table 1: 4.7 lesions/52 weeks × 243 patients = 22). The frequency of lesions in the UVR-exposed zone was less for the posttreatment episodes than for the primary delayed classical lesions (55% vs. 90%, respectively). While not a feature of this protocol, the development of immediate lesions (onset within 48 h of UVR exposure) was documented at the Utah site, and these findings are shown in figure 1.

Figure 1
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Figure 1

Development of 36 herpes labialis lesions after UV radiation (UVR) exposure among 54 drug- and placebo-treated patients with herpes labialis at Utah study site. Immediate lesions (0–2 days after UVR) shown by hatch-marked bars; delayed lesions (3–7 days after UVR) by solid bars. See the Methods section for basis for distinction between lesion groups. Famciclovir was only tested against delayed lesions in this study.

As shown in table 2, there was a trend toward fewer primary delayed lesions among all subjects receiving famciclovir compared with placebo recipients. This difference, however, did not reach statistical significance (71/183 [39%] vs. 31/60 [52%], P = .100). Posttreatment lesions tended to be more common among those given famciclovir, but the difference was not statistically significant (20/183 [11%] vs. 2/60 [3%], P = .117). The frequency of aborted lesions was similar across all treatment groups.

Figure 2
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Figure 2

Effect of treatment with 3 different doses of famciclovir or placebo on maximum herpes labialis lesion area of primary delayed classical lesions. Bars indicate median values. For differences between individual famciclovir and placebo treatment groups, adjusted for multiple comparisons, P = .380, .092, and .009 in order of increasing famciclovir dose. Drug effects were dose-proportional by linear regression (P = .040).

Figure 3
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Figure 3

Kaplan-Meier plot of time to herpes labialis lesion healing by patient assessment for 3 different doses of famciclovir and placebo. Healing time was measured from onset of vesicle stage to loss of hard crust.

Figure 4
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Figure 4

Hard crust duration by Kaplan-Meier time plot from onset of crust to loss of crust by patient assessment for 3 different doses of famciclovir and placebo.

Table 1
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Table 1

Demography and medication compliance for the total (intent-to-treat) study population.

Table 2
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Table 2

Proportion of patients with lesions.

Famciclovir treatment was associated with a marked reduction in mean maximum area of primary delayed classical lesions, which occurred in a dose-proportional fashion (figure 2). The increasing reduction in area with increasing dose was statistically significant when analyzed by linear regression (P = .040). The mean maximum area for the 500-mg famciclovir treatment group was less than half the mean maximum area in the placebo group (139 vs. 55 mm2, P = .009). The differences between the other 2 active treatment groups and placebo was not statistically significant. The differences in the median maximum lesion area were much less striking. As shown in figure 2, the basic effect of progressively higher doses of famciclovir on lesion area was to eliminate unusually large lesions (>175 mm2): 6, 5, 3, and 0 large lesions occurred in the placebo and 125-, 250-, and 500-mg famciclovir treatment groups, respectively.

Duration of classical lesions

As shown in table 3, the median time to healing of primary delayed classical lesions from the onset of the vesicle stage to loss of hard crust by investigator assessment at the time of the daily clinic visit occurred 1–2 days faster for the famciclovir treatment groups compared with placebo recipients. The difference in comparison with placebo was significant for the 500-mg group (2 days, 33% reduction; P = .010) but not for the other active treatment groups. Examination of dose-response by linear regression was not statistically significant. As shown in table 3, the median time to healing of primary delayed classical lesions from the onset of the vesicle stage to loss of hard crust by patient assessment 4 times a day occurred 1.1–2.8 days faster for the famciclovir treatment groups than for placebo recipients. The difference compared with the placebo group was significant for the 500-mg group (2.8 days, 48% reduction, P = .008) but not for the other active treatment groups. Examination of dose-response by linear regression was not statistically significant. The effect of treatment on patient-derived lesion healing times measured from the onset of the vesicle stage is illustrated in figure 3.

Table 3
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Table 3

Time to healing of primary delayed classical lesions from onset of vesicle.

Evaluation of the length of individual lesion stages showed that the median duration of the vesicle stage was reduced 0.65–1.0 day in the 500-mg famciclovir group compared with the placebo group (data not shown). The effect of therapy was most discernable on the median duration of the hard crust stage, which was smaller in a dose-dependent manner by patient assessment for the placebo and for the 125-, 250-, and 500-mg famciclovir treatment groups (3.34, 2.49, 1.39, and 0.67 days, respectively). When examined by linear regression, dose-dependence of the hard crust stage was statistically significant (P = .028). Hard crust length by Kaplan-Meier plot is shown in figure 4.

Lesion pain

There was a decreasing proportion of patients with pain from primary delayed classical lesions for the placebo and for the 125-, 250-, and 500-mg famciclovir treatment groups (93%, 95%, 88%, and 83%, respectively), but this trend in proportions was not statistically significant by linear regression among the 3 treatment groups (P = .18). None of the proportions for individual famciclovir doses was statistically significantly different from placebo. As shown in table 4, the median time to loss of pain from the beginning of pain was 1.1, 2.7, and 2.3 days faster for the 125-, 250-, and 500-mg famciclovir treatment groups, respectively, compared with placebo recipients; however, none of these differences from placebo was statistically significant. There was no evidence of a dose-response relationship for time to loss of pain by linear regression.

Table 4
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Table 4

Time to loss of pain from first occurrence of pain, patient assessment.

Virology

Of the 87 patients with primary delayed classical lesions, 84 had ⩾ 1 lesion swab taken for virus isolation. Among the sampled patients, a lower proportion of famciclovir recipients (59%) than placebo recipients (79%) had a positive virus culture, but this difference was of only borderline statistical significance (P = .09). None of the individual famciclovir dosing groups was significantly different from placebo, and there was no suggestion of a dose-response. Of the 55 patients who had a positive virus culture, most (35) only had 1 positive specimen, preventing an analysis of time to cessation of viral shedding.

Relationship of lesion severity measures to time of lesion onset

Because virus associated with lesions developing at a later time point after UVR exposure may theoretically have been exposed to drug longer either in the skin (earlier treatment) or in the ganglion (prophylaxis), we examined the relationship between lesion severity and time of lesion onset. For the combined drug-treated population, there was no relationship by linear regression between maximum lesion size and day of onset (r2 = .010, P = .469) or lesion healing time and day of onset (r2 = .001, P = .847).

Adverse reactions

Of the adverse experiences that were considered to be related or possibly related to study treatment, only headache and nausea occurred in ⩾5% of patients in any treatment group. There were no statistically significant differences in the frequency of headache or nausea between any of the famciclovir groups and the placebo-treated patients. One placebo-treated patient was withdrawn from the study due to adverse experiences (diarrhea, nausea) that occurred on-therapy and were considered related to study medication. There were no reports of serious adverse events on-therapy to within 30 days of last dose. While there were isolated laboratory study abnormalities, no consistent pattern or dose response was identified. The incidence of laboratory abnormalities was comparable between the 3 famciclovir groups and the placebo group.

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Discussion

Multiple trials of antiviral drugs for recurrent herpes labialis in otherwise normal, immunocompetent patients have been undertaken in the last 30 years [18, 23]. Many of these studies have yielded negative results and have been discouraging both to patients and investigators. Large-scale studies that have shown antiviral drug efficacy in the treatment of herpes labialis include trials of idoxuridine in dimethyl sulfoxide, peroral acyclovir, and penciclovir cream [21, 24–26]. Despite these advances, the treatment benefit has been modest, and there is a need to examine factors that could lead to improved efficacy. Whether higher doses might be beneficial is one factor that has not been systematically examined. In this trial, we showed that 500 mg of famciclovir 3 times a day for 5 days was superior to two smaller doses of the drug and effected a marked reduction in median lesion healing time, both by investigator (4 vs. 6 days, 33% reduction; P = .010) and patient assessment (3.0 vs. 5.8 days, 48% reduction; P = .008) analyses.

The UVR-induced model of recurrent herpes labialis used in this trial is a sensitive and expedient clinical test of therapeutic agents for this disease. In comparison with field trials of new therapies, because the time of onset of the recurrence in our model is always within a few days of enrollment, patient medication compliance and follow-up are excellent. UVR-induced lesions tend to be more severe, providing a larger “target” to test chemotherapy [27]. Experimental UVR-induced lesions can be divided into delayed and immediate lesions: The delayed lesions can be completely prevented with prophylactic antiviral therapy and have responded with reduced lesion severity to episodic treatment with topical or systemic antiviral agents [19, 20, 28]. Post-UVR immediate lesions have not responded to antiviral treatment. Whether there is an analogue to the post-UVR immediate lesions among naturally occurring lesions is possible but speculative [29]. Finally, treatment can be given preemptively 48 h after UVR exposure in the model, as in the present trial, to ensure the earliest possible initiation of chemotherapy for all lesions. In field trials, circumstances (e.g., sleeping hours and leaving the drug at home or in an automobile) often prevent or delay early treatment. Because of the advantages of the model, results of the same agent tested in field trials will likely show lesser efficacy.

In typical experimental UVR exposure protocols to date, therapy was begun before clinical lesion onset [19, 20, 28]. Initiation of therapy with an effective parenteral agent, such as acyclovir capsules, before or at the time of UVR exposure, completely prevents delayed lesions; however, if treatment is begun 48 h after UVR exposure, delayed lesions are not prevented but are less severe [19]. The first instance is prophylaxis, and lesions are prevented, in theory, because the systemic agent suppresses replication both in the neural ganglion, where reactivation is taking place, and in the skin [30]. The latter instance, where initiation of treatment is delayed and lesions can be ameliorated but not prevented, we consider a model of early, episodic intervention, or “preemptive” episodic therapy. We have assumed that virus replication in the ganglion occurs by 48 h and that therapy acts only on virus in the skin. Since virus-selective nucleoside antivirals, such as acyclovir and penciclovir, have no activity until epidermal cells are infected and viral thymidine kinase is synthesized, initiating metabolism of the drug to its active form, herpes lesions developing 3–7 days after UVR exposure, should all have equal drug exposure despite differences in the duration of therapy before lesion onset. To test these assumptions, we examined the activity of famciclovir in the present study as a function of lesion onset time after UVR exposure. No correlation was found between lesion healing time or maximum lesion area and time after UVR exposure.

The results of the present study show that lesion development (the number of lesions and the frequency of aborted lesions) was not reduced by preemptive therapy with any of the 3-dose regimens of famciclovir. While the same results have been consistently found in large clinical trials of nucleoside antivirals for the episodic therapy of herpes labialis [21, 24–26], the occasional small study with positive results [31] fuels the hope that this highly desirable clinical outcome might be achievable. Our present results, performed with high doses of antiviral drug under optimized conditions, provide additional strong evidence to the contrary. The pathogenetic aspects of herpes labialis that make it difficult to treat have been reviewed elsewhere [3].

Famciclovir treatment was associated with a marked reduction in mean maximum lesion area, which occurred in a dose-proportional fashion. The mean maximum area for the 500-mg famciclovir group was less than half the mean maximum area in the placebo group (139 vs. 55 mm2, P = .009). The differences in the median maximum lesion area were much less striking, and the basic effect of progressively higher doses of famciclovir on lesion area was to eliminate unusually large lesions. This effect has not been seen in large field trials of antiviral drugs for herpes labialis [21, 24, 25] but was noted in a prior trial of preemptive, episodic treatment in the experimental UVR herpes labialis model with acyclovir capsules [19]. There are two possible explanations for this difference. First, the earlier initiation of treatment in the preemptive episodic therapy design of the UVR model compared with field trials may enable antiviral therapy to affect lesion size. Second, 100% of the lesions, theoretically, in the UVR model are induced by radiation exposure compared with 20% of naturally occurring lesions [27]. UVR-induced lesions are more than twice as large as lesions developing from other stimuli [27], possibly because UVR-exposed skin is transiently immunocompromised through depletion or incapacitation of Langerhans cells [32]. Antiviral agents may be able to play a significant role in the restriction of lesion size in UVR-induced lesions, whereas lesions arising from other stimuli are prevented from spreading by an intact cutaneous immune system [3, 27].

This trial is the first dose-ranging study to be conducted in recurrent herpes labialis, and the results, perhaps paradoxically for a minor cutaneous infection due to a virus considered sensitive to penciclovir, show that large doses of famciclovir may be optimal therapy—doses in the range used for varicella-zoster virus infections. However, herpes labialis has been historically hard to treat, and there have been explanations for this phenomenon, based on the pathogenesis of the disease and the mode of action of nucleoside antiviral agents, along with a call for evaluation of higher drug doses [3, 4]. The data suggest that 500 mg of famciclovir 3 times a day for 5 days is the optimum dose. Higher doses were not explored, but they would be prohibitively expensive. There is only a small clinical advantage of 500 mg over 250 mg 3 times a day, and thus many patients may prefer the lower dose at half the cost. Lastly, it is not certain that antiviral therapy for 5 days is essential, since most viral replication occurs in the first 48 h [33]. Thus, the efficacy of shorter courses of treatment should be evaluated. How any of these regimens would compare with results with topical 1% penciclovir (Denavir; SmithKline Beecham), currently approved in the United States for recurrent herpes labialis, in not known.

Several dose-ranging studies have been reported for recurrent herpes genitalis. Two trials that compared 200- and 800-mg doses of acyclovir yielded mixed results [34, 35]. Goldberg et al. [34] found a greater benefit with 800 mg twice a day than with 200 mg twice a day among patients with recurrent genital herpes, while Wald et al. [35] found no difference between 800 or 200 mg 5 times a day for patients with first-episode genital herpes infection. There were no differences in efficacy between valaciclovir (1000 mg 2 times/day) and acyclovir (200 mg 5 times/day) among patients with recurrent genital herpes, despite 3-fold differences in daily drug concentration area under the curve favoring the prodrug [36, 37] or between 500 and 1000 mg of valaciclovir twice daily [38], suggesting that the peak plasma levels of acyclovir from these doses of valaciclovir were in an optimum range for this disease. The optimum trough level of acyclovir remains to be determined. Finally, Sacks et al. [39] compared 125, 250, and 500 mg of famciclovir twice a day for 5 days with placebo among 467 immunocompetent patients with recurrent herpes genitalis. All doses were equally effective. It is apparent from these data that herpes genitalis is an easier disease to treat than herpes labialis and can be managed with lower doses of antiviral agents. This conclusion is further supported by a large study that showed that the frequency of aborted lesions increased with episodic treatment of recurrent herpes genitalis with valaciclovir [38], a clinical outcome, as discussed above, that has eluded investigators treating herpes labialis.

In conclusion, we believe this study to be the first dose-ranging trial of antiviral chemotherapy for recurrent herpes labialis. We observed a 48% reduction in lesion healing time in a subgroup of subjects given 500 mg of famciclovir 3 times a day: the largest therapeutic benefit accomplished to date in this disease by antiviral chemotherapy. Although these results were obtained under experimental conditions, the findings suggest that evaluation of higher drug doses for herpes labialis treatment is warranted, using either the peroral route of administration or topical therapy in combination with skin penetration-enhancing agents.

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Footnotes

  • Each study participant signed an institutional review board-approved document of informed consent, and guidelines for human experimentation at each institution were followed.

  • Grant support: SmithKline Beecham Pharmaceuticals.

  • Received July 8, 1998.
  • Revision received September 30, 1998.
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  1. J Infect Dis. (1999) 179 (2): 303-310. doi: 10.1086/314605
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